CD8 + T cells, which are strongly induced by most viral infections, are conceptually attractive as effector cells in autoimmunity, because most cell types express MHC class I and are, therefore, open to CD8 + T cell surveillance. Many studies of autoimmune disease have focused on CD4 + T cells, but emerging data indicate that CD8 + T cells may play a critical role. In this component of the program grant, I focus on CD8 + T cells and, in particular, on their ability to undergo bystander activation during viral infections. We postulate two general types of virus-induced bystander activation, both of which will be investigated herein. First, we have evidence that, during virus infection, a substantial proportion of naive CD8 + T cells can undergo some degree of TcR-independent bystander activation. In Specific Aim 1, we shall: (i) evaluate how effectively naive, primary, and memory CD8 + T cells are activated in vivo in a TcR-independent manner; (ii) determine whether naive cells, activated by these bystander effects, mature into "bystander memory" cells; (iii) evaluate the roles of several cytokines in TcR-independent bystander activation. Second I propose a novel mechanism to explain TcR-dependent bystander activation. I suggest that virus-induced IFNgamma, up-regulates expression of the immunoproteasome and that this, in turn, leads to the presentation of new self epitopes, against which autoreactive CD8 + T cell responses may be mounted. Little is known about how, where & when the immunoproteasome is induced during virus infection, and this is the focus of Specific Aim 2. In Specific Aim 3, we shall evaluate the role of the immunoproteasome in type 1 diabetes. These studies will be carried out together with Dr. von Herrath (PI of this program grant, and of Project I). We shall determine immunoproteasome expression during the development of T1D, and assess whether T1D develops in the absence of the immunoproteasome. Finally, in Specific Aim 4, in collaboration with Dr. Fujinami (Project II), we shall study the role of the immunoproteasome in CNS autoimmune disease, including a new animal model of multiple sclerosis, in which CD8 + T cells appear to be the culprits.